The specific aims of the study are to: (1) prospectively evaluate adrenal function in patients with type 1 diabetes, or other autoimmune disorders and their relatives, found to express 21-hydroxylase autoantibodies and (2) correlate histocompatibility complex human leukocyte antigen (HLA) alleles and additional immunogenetic determinants with progression to Addison's disease. Addison's disease is a rare autoimmune disorder (<1/20,000), which is readily treated with glucocorticoid replacement, but a disorder which is so rare that not infrequently patients are diagnosed only after life threatening, or life ending adrenal crisis. Recognizing the association of Addison's disease with type 1 diabetes and the availability of a new autoantibody assay for anti-adrenal antibodies, we have screened approximately 1,000 patients with type 1 diabetes for the expression of 21-hydroxylase autoantibodies. To date, investigators have found more than 15 individuals with 21-hydroxylase autoantibodies without a known diagnosis of Addison's disease. Three of these individuals have now been diagnosed with overt Addison's disease, while the remainder do not have a major abnormality of adrenal function, but have not been studied with tests likely to detect subclinical abnormalities (plasma renin activity). At the same time, we have discovered a strong association of Addison's disease with a specific HLA allele, DRB1*0404, and in particular suggestive data, that progression to Addison's disease amongst patients with 21-hydroxylase autoantibodies is dependent upon this DRB1 histocompatibility marker. The present proposal is designed to better define adrenal function of patients with and without DRB1*0404, that express 21-hydroxylase autoantibodies, and importantly, will provide prospective information.